report inScientific Reports how a particular biochemical signaling pathway cancels biological noise, ensuring the proper stem cell differentiation during development. The conclusions are based on a combination of mathematical modeling and genetic experiments on fruit flies.

Noise is usually considered a nuisance, for example when preventing us from clearly hearing what someone is saying. The general concept of noise applies more broadly. In biology, the physical differences between organisms of the same type, for example two humans, originate from so-called developmental noise - ultimately stemming from probabilistic collisions between reacting molecules and environmental conditions in cells during the early stages of the organism's growth. Generally, mechanisms are in place to prevent biological noise from resulting in incorrect organismal developments. Makoto Sato from Kanazawa University and colleagues have now discovered that a particular biochemical signaling pathway contributes to noise cancelling in the differentiation process of neural stem cells - the self-renewing cells that play an important part in the development of the nervous system of animals during the embryonic stage.

As a model system for understanding cancellation mechanisms of biological noise in a multicellular organism, the researchers looked at a particular development stage of the visual system in fruit flies: the propagation of the so-called 'proneural wave', during which cells of a type called neuroepithelial cell differentiate into neuroblasts (cells in the process of dividing into neurons).

Inspired by earlier research, Sato and colleagues hypothesized that a signaling pathway (a particular chain of reactions between proteins in cells) known as JAK/STAT is involved in noise cancellation. The scientists combined mathematical modeling and genetic experiments. For the former, they designed a set of mathematical equations that quantify the variations in the system and reproduce the progression of the proneural wave. When including JAK/STAT signaling, they found that spontaneous, noise-induced neuroblast differentiation is cancelled.

To confirm the effect of JAK/STAT signaling in vivo, the researchers performed experiments wherein the signaling pathway was reduced in a controlled way. Upon reduction, stochastic differentiation of neuroblasts was observed, consistent with the conclusion that JAK/STAT has a noise-canceling function. Further genetic experiments provided more insights into the details of how noise canceling by JAK/STAT happens, and that this may be a function that has been conserved throughout evolution.

Not only does the work of Sato and colleagues contribute to a better understanding of noise-canceling mechanisms in developmental biology, it also underlines the power of combining 'in silico' with 'in vivo' studies. Quoting the scientists, "by applying a combination of mathematical modeling and molecular genetics, we can solve biological questions that have previously been difficult to address."

Background

JAK/STAT signaling pathway

The JAK/STAT signaling pathway (JAK stands for 'Janus kinase' and STAT for 'signal transducer and activator of transcription protein') comprises a series of reactions between proteins in a cellular environment. It plays a role in processes including immunity, cell division and death, and tumor formation. Disruption of the pathway can lead to diseases, including skin conditions, cancer and immune system disorders. The JAK/STAT pathway also has an important role in the development of animals. In the fruit fly, it is crucial for the development of the eyes.

Makoto Sato from Kanazawa University and colleagues have now performed experiments and mathematical modeling on the eye development of the fruit fly, showing that the JAK/STAT signaling pathway functions as a biological-noise canceller.

Propagation of the proneural wave, in vivo, in the visual system of a developing fruit fly.

About Kanazawa University

As the leading comprehensive university on the Sea of Japan coast, Kanazawa University has contributed greatly to higher education and academic research in Japan since it was founded in 1949. The University has three colleges and 17 schools offering courses in subjects that include medicine, computer engineering, and humanities.

The University is located on the coast of the Sea of Japan in Kanazawa - a city rich in history and culture. The city of Kanazawa has a highly respected intellectual profile since the time of the fiefdom (1598-1867). Kanazawa University is divided into two main campuses: Kakuma and Takaramachi for its approximately 10,200 students including 600 from overseas.

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